Transdermal therapeutic systems are administration forms which have a layered structure and comprise at least one active ingredient-containing polymer layer and one active ingredient-impermeable backing layer. Transdermal therapeutic systems are also referred to as active-ingredient patches. They permit long-lasting administration of the pharmaceutical active ingredient contained therein to the skin or via the skin of a patient to be treated.
For transdermal administration of active ingredients via the skin in a therapeutically necessary dose, the active ingredient to be administered must have sufficient skin permeability. Therefore, for the purposes of developing transdermal therapeutic systems, active ingredients in the form of their free base (active-ingredient base) are preferably used. Active-ingredient bases usually have good permeation properties for transdermal administration which are considerably better than those of the salts of the corresponding active ingredient. In addition, active-ingredient bases can be easily processed during preparation of active ingredient-containing masses for transdermal preparations. Also, owing to their rapid availability in transdermal therapeutic systems, active ingredients in the form of their free base are used preferentially over the salts of the corresponding active ingredient.
For the resulting transdermal preparations, there are further advantages: the weight of the matrix is lower and/or the active-ingredient concentration in the matrix can be lower, the concentration of permeation enhancer can be reduced or permeation enhancers can be completely omitted, and it is possible to produce transdermal therapeutic systems having other adhesive properties.
However, production of transdermal therapeutic systems having an active ingredient in the form of its free base, and transdermal therapeutic systems having an active ingredient in the form of its free base, can also have disadvantages. For instance, the active-ingredient base must be stored at low temperatures, i.e., at 4° C. or at lower temperatures, to avoid undesired degradation of the active ingredient. Storage at low temperatures is also advisable when the active-ingredient base is highly volatile, in order to prevent the pressure in the container storing the active-ingredient base from becoming too great.
Problems may also occur when preparing active ingredient-containing masses or when coating support materials with said active ingredient-containing masses. If use is made of an active-ingredient base having a high vapor pressure (e.g., identifiable by a low evaporation number), this may result in considerable losses of active ingredient during coating and subsequent drying of the preparation.
In addition, antioxidants often need to be used to stabilize the active-ingredient base, in order to prevent or to at least reduce interactions between the active-ingredient base and other constituents of the transdermal therapeutic system, for example the pressure-sensitive adhesive, the permeation enhancer, the excipients, the backing layer or the protective sheet.
Undesired interactions between an active-ingredient base and ambient air are also possible. For instance, the moisture in the air may lead to hydrolysis of the active-ingredient base. However, an undesired reaction between the active-ingredient base and the moisture in the air can only be avoided by a complicated production process in which the transdermal therapeutic systems are sealed in the packaging material pouch without intermediate storage and with introduction of an inert gas, for example nitrogen or helium, instead of ambient air.
Besides the aforementioned chemical stability problems associated with the use of an active-ingredient base, physical stability problems may also occur. The matrix of a formulation in which an active-ingredient base is used instead of a corresponding active-ingredient salt is often already very soft immediately after coating. Provided that the adhesiveness would rise even further after coating, it is often necessary to add additional matrix formers as early as during the preparation of the active ingredient-containing masses, so that the transdermal therapeutic system at the end of its period of application can be completely removed from the skin.
In addition, transdermal therapeutic systems having an active-ingredient base may see the occurrence of marked “cold flow”, which causes the systems to adhere to the interior of their packaging or makes application and wearing of the system difficult.
The aforementioned problems with developing and producing transdermal therapeutic systems can be avoided at least in part if an active-ingredient salt is used instead of the free active-ingredient base. The use of active ingredients in the form of one of their pharmaceutically acceptable salts for transdermal therapeutic systems is advantageous in that the transdermal therapeutic systems respond more insensitively to external influences, chemical stability is better because the active-ingredient salt has fewer interactions with other ingredients or components of the system, and “cold flow” is reduced.
However, the skin permeability of pharmaceutical active ingredients in the form of a salt is substantially worse than the skin permeability of the free base of said active ingredient, and so many active-ingredient salts are not suitable for administration via the skin in a therapeutically necessary dose using a transdermal therapeutic system.
However, in order to adjust the flux rate of a transdermal therapeutic system to a certain level, i.e., to limit it, active ingredients with good skin permeability generally need a control membrane which is arranged between the skin and the active-ingredient reservoir. However, such transdermal therapeutic systems require a complicated development and production process, and so the costs for the production of the systems are high. In addition, the physical properties of the system such as flexibility and adhesiveness change as a result of the addition of the control membrane.